Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 CMU - Carnegie Mellon University [Pittsburgh]
4 HMS - Harvard Medical School [Boston]
5 UC San Francisco - University of California [San Francisco]
6 UCLA - University of California [Los Angeles]
7 University of Pittsburgh School of Medicine
8 MSSM - Icahn School of Medicine at Mount Sinai [New York]
9 NPS - Neuroscience Paris Seine
10 UNITO - Università degli studi di Torino = University of Turin
11 Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
12 HKU - The University of Hong Kong
13 UIC - University of Illinois [Chicago]
14 UMMSM - University of Miami Leonard M. Miller School of Medicine
15 UNITN - Università degli Studi di Trento = University of Trento
16 UC Irvine - University of California [Irvine]
17 Nationwide Children's Hospital
18 UC Davis - University of California [Davis]
19 Universidade do Minho = University of Minho [Braga]
20 Massachusetts General Hospital [Boston, MA, USA]
21 POLI-USP - Escola Politécnica [Universidade de São Paulo]
22 UniMe - Università degli Studi di Messina = University of Messina
23 UNISI - Università degli Studi di Siena = University of Siena
24 Azienda Ospedaliera Universitaria Senese
25 Vanderbilt University [Nashville]
26 Vanderbilt University School of Medicine [Nashville]
27 UNIVR - Università degli studi di Verona = University of Verona
28 University of Texas Health Science Center
29 UCBM - Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
30 Emory University School of Medicine
31 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
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Résumé
Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
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